Neuropeptide somatostatin analogs are important therapeutics for the treatment of hormone secreting tumors with annual sales of ~$1.7B. However, the currently available peptide depots are effective in only half the patients with growth hormone secreting tumors, and patients with carcinoids can rapidly become resistant to these drugs. Somatostatin analogs act by stimulating sst2A, a G protein coupled receptor, but the currently available agents cause desensitization via internalization of the receptor, resulting in reduced or complete loss of efficacy. We hypothesized that biased agonists of the somatostatin receptor that maintain strong Gi activation, but do not cause desensitization, would normalize hormone levels in a greater percentage of patients and improve efficacy in patients not adequately controlled by currently available agents. In Phase I, we proposed to validate this hypothesis, using assays for both receptor activation and internalization to identify new nonpeptide, orally-active somatostatin biased agonists that do not cause desensitization, with the goal of providing improved therapeutic options for patients with these tumors. In Phase I, we identified several small molecule agonists that are indeed potent activators of Gi, but with far less propensity for, or no evidence of inducing receptor internalization and desensitization. These proof of concept studies showed that we can identify compounds with the desired profile using our assay cascade, and can support the medicinal chemistry lead optimization efforts required to identify a candidate suitable for clinical development. In Phase II, we will optimize our leads identified in Phase I to deliver a novel orally available drug candidate, which meets our defined criteria, to undergo the non-clinical toxicology studies necessary to support clinical development. In addition to improved clinical efficacy, orally delivered agents would also reduce the need for physician office visits, eliminate the pain and discomfort of depot injections, and lower the manufacturing costs compared to expensive peptide depot formulations. This project promises to deliver a new cost effective therapeutic agent with a novel pharmacological profile that leads to improved efficacy. Our approach towards the identification of such an agent is innovative in that we are incorporating receptor regulatory assays (to detect receptor desensitization), in addition to affinity (or activity-based) assays. This combination of assays wil be used to guide lead optimization efforts. Importantly, the G protein coupled receptor family is the largest gene family in the human genome and a rich source of proven targets for drug discovery, which share common regulatory and signaling mechanisms. Therefore, if successful, this work will not only provide improved agents for patients with hormone secreting tumors, but will also support a general novel strategy for optimizing agonist drugs that can be exploited to target many other GPCRs.